Normal bones are living tissues undergoing constant resorption and redeposition of calcium, with the net effect of maintenance of a constant mineral balance. The dual process is commonly called "bone turnover". In normal growing bones, the mineral deposition is in equilibrium with the mineral resorption, whereas in certain pathological conditions, bone resorption exceeds bone deposition, for instance due to malignancy or primary hyperparathyroidism, or in osteoporosis. In other pathological conditions the calcium deposition may take place in undesirable amounts and areas leading to e.g., heterotopic calcification, osteoarthritis, kidney or bladder stones, atherosclerosis, and Paget's disease which is a combination of an abnormal high bone resorption followed by an abnormal calcium deposition.
U.S. Pat. No. 4,621,077 to Istituto Gentili discloses a method of treating urolithiasis and inhibiting bone reabsorption by the use of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (also named 4-amino-1-hydroxybutane-1,1-bisphosphonic acid) and its salts with an alkali metal, an organic base or a basic amino acid. The compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is described as being between 100 and 300 times more active than dichloromethane-biphosphonic acid in inhibiting bone reabsorption.
Alendronate sodium, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium trihydrate, is an agent for combating bone resorption in bone diseases including osteoporosis and is described as a composition, method of use and synthesis along with other pharmaceutically acceptable salts in U.S. Pat. Nos. 4,922,007 and 5,019,651 (both assigned to Merck).
However, new crystalline forms of alendronate sodium are constantly being searched for to enable ease of formulation and better pharmacokinetics, e.g., desirable crystal habit, good flow properties, higher solubility, longer duration or quicker onset of action, and improved bioavailability. Particularly what is desired is a new formulation to overcome the gastric irritability associated with the administration of the free acid form of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. This is of particular importance in cases where the patient has a history of gastrointestinal problems prior to recommended alendronate therapy.